Nephropathy and Hypertension in Diabetic Patients

Carl Erik Mogensen

Medical Department M (Diabetes and Endocrinology), Kommunehospitalet, Arhus University Hospital, Arhus, Denmark

Introduction

Strict and steady near normoglycemia over many years is of paramount importance for the prevention and postponement of renal disease, as well as other complications in most patients with type 1 and type 2 diabetes. Later, several other factors appear to affect progression in renal disease of which blood pressure (BP) elevation seems most important. This seems also to be the case for macrovascular complications along with dyslipidemia, smoking and, as mentioned, hyperglycemia. Incipient renal disease in diabetes, as judged by the occurrence of microalbuminuria, is frequently characterized by hypertension starting with increase in BP from a normal level. The increase, however, is often subtle and may only be detectable by careful and continuous monitoring, e.g. by 24-hour ambulatory recordings. Elevation of BP is found in both types of diabetes, but there appear to be several distinctions between type 1 and type 2 diabetes; some of these variations are clearly explained by the different etiology and nature of the diabetic state. In type 2 diabetic patients, higher age, increased body weight, as well as syndrome X abnormalities are important factors. Though hypertension secondary to renal dysfunction is also frequently seen in type 2 diabetic patients, the renal genesis of hypertension is much clearer and more common in the relatively younger type 1 diabetic patients. Indeed a vicious circle seems to be operating in both types of diabetes and differences between type 1 and type 2 diabetes regarding nephropathy are far fewer than reported earlier. It should be noted that dietary protein intake may also be a modulating factor, but further studies on intervention are needed. These factors - glycemic control, BP elevation and to some extent dietary proteins, and the modification by treatment - will be the main issues for discussion here.

BP, Glomerular Pressure and Potential Genetic Factors

In the past decades there has been a growing interest in the nature of diabetic renal disease, mainly focusing on BP, glomerular pressure and protein leakage as related to structural and biochemical abnormalities. A recently published volume intends to cover almost every aspect of renal disease and hypertension in diabetes. One key point is interesting here; in general, two or more risk factors must coincide to provoke fast and serious organ damage. In terms of diabetic nephropathy this means that some degree of poor glycemic control may not always be clinically noxious enough per se, unless some other risk factors, especially elevated BP or possibly poorly defined genetic elements coexists. However, increased glomerular pressure seems to be a decisive factor, whether caused directly by poor glycemic control, dietary proteins or systemic hypertension, in particular with loss of renal vascular autoregulation that may be seen in diabetes. Other risk factors may contribute to renal and especially vascular damage in diabetes, e.g. smoking, lipid abnormalities or obesity, again highlighting the importance of the metabolic syndrome, or syndrome X mainly in type 2 diabetes.

Diabetic renal disease may tend to cluster in families, possibly partly reflecting that poor metabolic control also predominates in certain families. This could also relate to ACE gene or other gene polymorphism, but genetic association to diabetic renal disease and its progression may not be strong and has recently been challenged. From a clinical point of view, ACE genotyping is hardly relevant. Based on a meta-analysis, Tarnow et al. concluded that the ACE/ID polymorphism may contribute to the genetic susceptibility to diabetic nephropathy in Japanese type 2 diabetic patients, whereas it does not play a major role in the initiation of diabetic nephropathy in Caucasian type 2 patients. In Caucasian type 1 diabetic patients, comparison of data is complicated by differences between study populations, but a trend towards a protective effect of the II genotype on the development of increased urinary albumin excretion rate was observed, but there is considerable overlap between genotypes. However, a progression also during antihypertensive treatment is somewhat faster with the DD genotype. Whether this is related to actual BP during treatment is unclear.

Comparing the different risk factors - apart from poor metabolic control - BP elevation seems to be not only the most important index of actual or subsequent organ damage, but also the most readily measurable (sometimes

Fig. 1. Interplay of genetics and risk factors.

with 24 h ambulatory BP) as well as modifiable risk factor (fig. 1). Virtually all studies agree that standard medical antihypertensive treatment is able to reduce BP in diabetes, and many studies have confirmed the original observations of a beneficial impact of antihypertensive treatment on the course of renal disease, both in incipient and overt type 1 diabetic patients. Interestingly, ACE inhibitors may be particularly beneficial, although this has been questioned by some. Certainly, the side effect profiles usually favor the use of these agents often combined with diuretics both in incipient and overt nephropathy. These considerations also apply to cardiovascular events in hypertensive type 2 diabetic patients. Combination therapy including p-blockers often has to be used to reduce BP as well as albuminuria efficiently.

Changing Cumulative Incidence of Renal Disease in Diabetes

The cumulative incidence of diabetic nephropathy used to be high («35%) but seems to have declined over recent years, especially in certain areas where only very few patients in a given cohort developed nephropathy. However, this observation could not be confirmed by other groups. The explanation is not clear, but certainly the so-called natural history may be considerably modified by more intensive intervention throughout the course of diabetes. To a large extent, this relates to metabolic control and BP elevation as major factors, but other issues are of importance, e.g. smoking, that may vary considerably. Also race is of importance and diabetic nephropathy is more commonly seen in African-Americans. Indeed new studies among the Pima Indians suggest that with long follow-up periods practically all patients will develop renal disease. This information is important because it has been suggested that there may be important susceptibility factors that could relate to genetics. Comparison has been made to eye diseases where practically all patients sooner or later develop lesions. However, there are important modifications since usually renal disease is judged by albuminuria and not by morphology, e.g. on biopsies, and in fact the cumulative incidence of diabetic retinopathy and nephropathy could be almost the same, if histological as well as ophthalmologic examinations are used. It has also been discussed why some people seem to escape diabetic nephropathy even if they are in poor control. A feasible explanation is that in order to produce important clinical disease two factors must be present, namely high BP as well as high glucose. If the combination of high BP and high blood glucose is present the clinical experience is that almost all patients will develop clinically relevant nephropathy and also retinopathy.

Recent studies underscore the role of good metabolic control also in more advanced nephropathy. This has been documented in several studies, and also recently by Mulec et al. These results are in concert with information from Denmark, Gothenburg and London. Clearly with advanced nephropathy elevated BP is of importance, and combining the two risk factors in overt nephropathy, huge differences in progression may be observed. With poor control of glycemia and especially poor BP control, the fall rate is high («10-12 ml/min/year or even more), but with efficient control of blood glucose and BP fall may be close to 1-2 ml/year which is close to the age-related reduction. Obviously, it is not possible to obtain perfect metabolic control in all patients, especially in those at risk or with nephropathy because the very background for developing complications is the poor control which may not be easy to modify even after development of complications. This is exemplified in a study from the UK, The Microalbuminuria Collaborative Study. The combined deleterious effect of poor glycemic control and BP control is indeed also clear from the important UKPDS intervention study in type 2 diabetes.

In summary, one could argue that the concept of 'natural history' may be wrong unless it is used specifically in patients who are in specifically defined glycemic control. However, if risk factors such as hyperglycemia and BP elevation can be controlled, few patients may actually develop proteinuria and eventually end-stage renal disease both in type 1 and type 2 diabetes. Also with advanced nephropathy, glycemic control seems very important.

However, an intensified strategy requires considerable resources not only from the health-care providers but also from the patients. The recent Steno Study used the new concept of multifactorial intervention with a good result on renal and retinal diseases. It may be easier to implement long-term treatment with ACE inhibitors or other antihypertensive agents, also in the normoalbumi-

nuric state as recently proposed by Ravid et al. However, both strategies should be exercised in the clinical setting as discussed below.

Notes on Key Risk Factors: Blood Glucose

Perfect metabolic control, that is blood glucose as well as concentrations of other metabolites and hormones within normal range, is presently almost impossible to obtain in the majority of diabetic patients. Even in the DCCT (The Diabetes Control and Complications Trial Research Group) optimized management in type 1 diabetic patients only rarely resulted in perfect glycemic control. The same may be the case in type 2 diabetes, where a somewhat better control may be possible. Under standard care conditions, HbA1c values may be 50% or most often even higher than normal reference values in most patients. However, good metabolic control remains a key factor in preventing retinopathy and nephropathy, and progression of nephropathy, also when severe damage is present after fall in GFR. Further long-term studies are needed in type 2 diabetic patients but the same relation seems to exist here, especially early in the course of the renal disease. Long-term renal data from the UKPDS would be highly interesting.

Notes on Key Risk Factors: BP Level in Treated Diabetes

Nowadays very high BP levels are rarely observed in the clinic in treated diabetic patients. High pressures are most often encountered in populations without any structured care for complications. With appropriate antihypertensive programs the degree of elevation of BP is usually not very pronounced at least when compared to the past. This is for instance corroborated by new studies where 24hour BP recordings in diabetics are carefully compared to nondiabetics. When diabetics who do not receive antihypertensive treatment are selected, it is obvious that BP elevation is not pronounced, around 5 mm Hg on average in microalbumi-nuric patients. Clearly such data are biased, because patients who are already in treatment are excluded. On the other hand, even minor BP elevation may lead to vascular and glomerular damage, especially when accompanied by other risk factors, e.g. hyperglycemia. A correlation exists between albuminuria and BP and the association is amplified when 24 ambulatory BP values are used rather than conventional BP measurements. Diabetic patients may be exquisitely susceptible to systemic BP elevation because the normal protection exerted by the afferent renal arteriolar vasculature is likely to be compromised in many diabetic patients, and a vicious circle will develop in such conditions.

A few decades ago, BP elevation was usually much higher. A very pronounced fall in recorded BP has been observed in diabetes clinics during recent years, as evidenced by a Danish study, where BP levels in cohorts of patients in the 1960s were compared to patients in the 1980s.

Interesting differences exist between the two types of diabetes. In type 1 diabetes the prevalence of hypertension is strongly correlated with the degree of albuminuria. With normal albumin excretion rate, BP is close to normal which has been confirmed in recent studies using 24-hour BP recordings. With the occurrence of microalbuminuria there is a considerable increase in the prevalence of elevated BP, and even more marked changes are seen with overt diabetic nephropathy.

In type 2 diabetes the situation is more variable, although there is usually some association between albuminuria and BP level. However, the correlation is weaker, and it is also important to recognize that the prevalence of BP elevation is much higher in the elderly type 2 diabetic patients; even at the time of clinical diagnosis about 40% of patients had elevated BP or were receiving antihypertensive treatment. In a control population without diabetes this figure may be 20%. Interestingly BP elevation in type 2 diabetic patients is usually of systolic nature, at least in some studies. Effective treatment may be difficult with high initial values and therapeutic goals should be modified, with a stepwise reduction in BP.

Without treatment the rate of increase in BP with time is recorded to be high in type 1 diabetic patients with microalbuminuria or overt proteinuria, supporting the idea that a self-perpetuating process exists. This increase is most pronounced in type 1 diabetic patients; clear data are more difficult to obtain in type 2 diabetes, because so many patients are treated with antihyper-tensive drugs and discontinuation of treatment is not justifiable. Still an increase is seen, especially with 24-hour monitoring. In type 1 diabetes, BP may increase by 3-4 mm Hg/year with microalbuminuria, and around 6 mm Hg/year with overt renal disease. Such data may be difficult to reproduce today, simply because so many patients are early and effectively treated.

Notes on Key Risk Factors: Dietary Proteins

With some variations from country to country, traditional diabetic dietary management often results in a high protein intake (sometimes 50% higher than the average background population). This may not be an appropriate strategy because a dietary pattern like that may aggravate the course of renal disease.

Microalbuminuria as an Important Intermediary Endpoint

A major question in all types of clinical management is to define parameters that can be considered important markers in terms of disease activity. This is of special importance in intervention trials, but also in the treatment of patients, where results from already conducted trials are rapidly reflected in practical management. An outline of the natural history of renal disease in type 1 diabetic patients is given in table 1.

Hypertensive and proteinuric diabetic patients usually carry a very poor prognosis. It has also become clear that abnormal albuminuria in the microal-buminuric range (20-200 ^g/min) is an important long-term predictor for poor outcome. A decisive parameter is the fall rate of GFR as measured by exact and reproducible techniques. Doubling of S-creatinine has also been used. Obviously, an even more solid endpoint is end-stage renal failure (ESRF) and/or death, but in patients with early clinical proteinuria or microalbuminu-ria, this is (fortunately) a distant endpoint since the development of ESRF may last at least one or two decades, especially after it has been shown that antihypertensive treatment postpones end-stage renal disease.

Strong evidence suggests that abnormal albuminuria (even slight elevation) is a key parameter and an important intermediary endpoint in the monitoring of all diabetic patients, not only because it relates so closely to the more advanced endpoints, but also because this parameter can be used both in the treatment strategies in controlled clinical trials, and in the day-today management of patients. Importantly, new studies show that glomerular structural damage can be arrested by early antihypertensive treatment (P-blockers or ACE inhibitors) in microalbuminuric patients. This is an extremely important finding again supporting the use of early antihypertensive medication.

GFR Fall in Type 1 Diabetes Related to Abnormal Albuminuria and/or BP Elevation

Patients with completely normal albumin excretion rate usually preserve normal renal function (GFR) over many years, at least one or two decades. It should be noted here that there may, however, be a small probably age-related reduction in GFR. Also patients with persistent microalbuminuria usually maintain intact GFR, though a subsequent fall in GFR can be predicted, with progression to macroalbuminuria and possibly partly related to previous hyperfiltration. Only with the development of proteinuria (ma-croalbuminuria) is there a significant decline in GFR. Antihypertensive treatment may reduce or even normalize albumin excretion, and thus lead to misclassification of patients. Albumin excretion may again increase if treatment is stopped for some reason. Feldt-Rasmussen et al. observed a significant drop in GFR with the development of clinical nephropathy but most of their patients received antihypertensive treatment which modifies the level of UAE

Table 1. Stages in the development of renal changes and lesions in diabetes mellitus (mainly type 1 or younger type 2)

Stage Chronology Main structural Glomenular Dextran clearance Albumin exception Blood pressure Reversible by strict Arrestable or changes or lesions filtration rate (%ofGFR) --insulin treatment reversible by

AHTb baseline UAEa exercise-

induced UAE

1 Acute renal Present at hypertrophy- diagnosis of hyperfunction diabetes

(reversible with good control)

2 Normo- Almost all albuminuria patients normo-(UAE < 20 |ig/ albuminuric in min) first 5 years

3 Incipient diabetic Typically after nephropathy, 6-15 years UAE 20-200 pg/ (in «35% of min patients)

4 Proteinuria, clinical overt diabetic nephropathy

After 15-25 years (in «35% of patients)

5 End-stage renal Final outcome, failure after 25-30

years or more

Increased kideney size Increased glomerular size

On renal biopsy, increased BM thickness

Further BM thickening and mesangial expansion, arrestable with AHT

Clear and pronounced abnormalities

Glomerular closure and advanced glomerulopathy

Increased by 20-50%

Increased by 20-50%

Still supra- Normal normal values, predicted to decline with development of proteinuria

Decline «10 Abnormal to ml/min/year with clear proteinuriac

< 10 ml/min Not studied

May be increased, but reversible

Increased, but reversible

Normal by definition May be Normal (BP as

(15-20 |ig/min may abnormal after in background be abnormal) a few years population)

Increase by 1 mm Hg/year

Increase «20%/year Abnormal Incipient

(of glomerular aggravation of increase, «3

origin) baseline UAE, mm Hg/year related to BP (if untreated)

high molecular dextrans (nonspecific and only with low GFR)

Progressive clinical proteinuriac of glomerular origin

Often some decline due to nephron closure

Hyperfiltration reduced

Microalbuminuria stabilized, GFR also stable (if HbAk is reduced). Structural damage slower

Higher fall in GFR

Pronounced High BP, increase in BP increase by « 5 with poor control mm Hg/year (if untreated)

Not studied High

(if untreated)

No hypertension present

Microcirculatory changes modifiable

Filtration fraction and UAE may be reduced

Microalbuminuria reduced

Prevention of fall in GFR

Progression reduced (aiming at 135/85 mm Hg)

BM = Basement membrane; UAE = urinary albumin excretion rate; AHT = antihypertensive treatment.

a The best clinical marker of early renal involvement.b Mostly ACE inhibition + diuretics.c Without antihypertensive treatment.

Nephropathy and Hypertension in Diabetic Patients

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